Methods of inhibiting CNS problems in post-menopausal women

ABSTRACT

A method of inhibiting one or more CNS disorders in a post-menopausal woman comprising administering to a female human in need of treatment an effective amount of a compound having the formula                    
     wherein R 1  and R 3  are independently hydrogen,                    
     wherein Ar is optionally substituted phenyl; 
     R 2  is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

BACKGROUND OF THE INVENTION

In climacteric women, anxiety, depression, tension and irritabilitybegin during the perimenopause and can be correlated to reduced estrogenlevels and estrogen replacement therapy has been recommended for thetreatment of these symptoms (Malleson J., Lancet, 2: 158, (1953); Wilsonet. al., J. Am. Geriatric Soc., 11: 347 (1963)). The mechanism forprotective effects of estrogen in this case is unknown, but may berelated to potential effects of estrogen on biogenic amines such asserotonin (Aylward M., Int. Res. Communications System Med. Sci., 1: 30(1973)). To this regard circulating serotonin is reduced inpost-menopausal women (Gonzales G., et. al., Maturitas 17: 23-29(1993)), and serotonin (as well as several other biogenic amines) have aputative role in behavioral depression.

Phillips and Sherwin (Psychoneuroendocrinology, 17: 485-495 (1992))reported that in surgically menopausal women given estrogen, scores inimmediate and delayed recall tests are greater than in similar women notgiven estrogen. Two potential hypotheses might explain this effect.There is some evidence that partial estrogen agonists (oranti-estrogens) such as tamoxifen interact with the muscarinic receptor(Ben-Baruch G., et. al., Molec. Pharmacol. 21: 287-293 1982), andmuscarinic agonists (M₂) are known to produce positive effects in anumber of memory associated tasks and may have clinical relevance inAlzheimer's Disease. Another interesting possibility may be linked toneurokinins such as Substance P, which are known to have neurotrophic aswell as memory-promoting effects (Thoenen H., Trends in Neuroscience,14: 165-170 (1991); Huston J. et. al., Neurosci. Biobehav. Rev. 13:171-180 (1989)), thus, through an effect either at a neurotransmitterreceptor in the CNS or at a neuropeptide receptor, a tissue selectiveestrogen agonist/antagonist could produce memory and cognitive enhancingeffects. Such an activity would most relevantly be assessed in man, buta variety of animal models (i.e. maze learning, extinction etc.) areavailable for preclinical testing.

Perhaps the most frequent CNS related problem in climacteric women isthe occurrence of hot flushes. While this undoubtedly is a somaticeffect mediated by effects on the microvasculature, current evidencepoints strongly in the direction of CNS initiated effect (Lomax P., et.al., Pharmac. Ther. 57: 347-358 (1993)). Therefore, a tissue selectiveestrogen agonist/antagonist like raloxifene might offer the idealtherapy providing the desired effect in the absence of untoward sideeffects on reproductive tissue.

SUMMARY OF THE INVENTION

This invention provides methods for inhibiting CNS problems in apost-menopausal female comprising administering to a female human inneed of treatment an effective amount of a compound of formula I

wherein R¹ and R³ are independently hydrogen,

wherein Ar is optionally substituted phenyl;

R² is selected from the group consisting of pyrrolidino,hexamethyleneimino, and piperidino; and pharmaceutically acceptablesalts and solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The current invention concerns the discovery that a select group of2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I,are useful for inhibiting CNS disorders in a post-menopausal woman. Themethods of treatment provided by this invention are practiced byadministering to a human in need of a dose of a compound of formula I ora pharmaceutically acceptable salt or solvate thereof, that is effectiveto inhibit one or more CNS disorders. The term inhibit is defined toinclude its generally accepted meaning which includes prophylacticallytreating a human subject to incurring the characteristics described, andholding in check and/or treating existing characteristics. As such, thepresent method includes both medical therapeutic and/or prophylactictreatment, as appropriate. CNS disorders are those disorders known to beincluded in the definition by those skilled in the art, which affectpost-menopausal women, which includes anxiety, depression, mood swings,tension, irritability, motivational defects, memory loss and cognitivedisorders.

Raloxifene, a compound of this invention wherein it is the hydrochloridesalt of a compound of formula 1, R¹ and R³ are hydrogen and R² is1-piperidinyl, is a nuclear regulatory molecule. Raloxifene has beenshown to bind to the estrogen receptor and was originally thought to bea molecule whose function and pharmacology was that of an anti-estrogenin that it blocked the ability of estrogen to activate uterine tissueand estrogen dependent breast cancers. Indeed, raloxifene does block theaction of estrogen in some cells; however in other cell types,Raloxifene activates the same genes as estrogen does and displays thesame pharmacology, e.g., inhibit bone loss, lower serum lipids. As aresult, raloxifene has been referred to as an anti-estrogen with mixedagonist-antagonist properties. The unique profile which raloxifenedisplays and differs from that of estrogen is now thought to be due tothe unique activation and/or suppression of various gene functions bythe raloxifene-estrogen receptor complex as opposed to the activationand/or suppression of genes by the estrogen-estrogen receptor complex.Therefore, although raloxifene and estrogen utilize and compete for thesame receptor, the pharmacological outcome from gene regulation of thetwo is not easily predicted and is unique to each. This is not to say,however, that the mechanism of action is necessarily mediated either atall or in part, through the estrogen receptor per se.

Generally, the compound is formulated with common excipients, diluentsor carriers, and compressed into tablets, or formulated as elixirs orsolutions for convenient oral administration, or administered by theintramuscular or intravenous routes. The compounds can be administeredtransdermally, and may be formulated as sustained release dosage formsand the like.

The compounds used in the methods of the current invention can be madeaccording to established procedures, such as those detailed in U.S. Pat.Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporatedby reference herein. In general, the process starts with abenzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl)group. The starting compound is protected, acylated, and deprotected toform the formula I compounds. Examples of the preparation of suchcompounds are provided in the U.S. patents discussed above. Substitutedphenyl includes phenyl substituted once or twice with C₁-C₆ alkyl, C₁-C₄alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.

The compounds used in the methods of this invention formpharmaceutically acceptable acid and base addition salts with a widevariety of organic and inorganic acids and bases and include thephysiologically acceptable salts which are often used in pharmaceuticalchemistry. Such salts are also part of this invention. Typical inorganicacids used to form such salts include hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.Salts derived from organic acids, such as aliphatic mono anddicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, may also be used. Such pharmaceutically acceptable saltsthus include acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. A preferred salt is thehydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I with an equimolar or excess amountof acid. The reactants are generally combined in a mutual solvent suchas diethyl ether or benzene. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

Bases commonly used for formation of salts include ammonium hydroxideand alkali and alkaline earth metal hydroxides, carbonates, as well asaliphatic and primary, secondary and tertiary amines, aliphaticdiamines. Bases especially useful in the preparation of addition saltsinclude ammonium hydroxide, potassium carbonate, methylamine,diethylamine, ethylene diamine and cyclohexylamine.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

Pharmaceutical formulations can be prepared by procedures known in theart. For example, the compounds can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; moisturizing agents such as glycerol; disintegrating agentssuch as calcium carbonate and sodium bicarbonate; agents for retardingdissolution such as paraffin; resorption accelerators such as quaternaryammonium compounds; surface active agents such as cetyl alcohol,glycerol monostearate; adsorptive carriers such as kaolin and bentonite;and lubricants such as talc, calcium and magnesium stearate, and solidpolyethyl glycols.

The compounds can also be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for instance by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular part of the intestinaltract, possibly over a period of time. The coatings, envelopes, andprotective matrices may be made, for example, from polymeric substancesor waxes.

The particular dosage of a compound of formula I required to inhibit oneor more CNS disorders in a post-menopausal female, according to thisinvention, will depend upon the severity of the condition, the route ofadministration, and related factors that will be decided by theattending physician. Generally, accepted and effective daily doses willbe from about 0.1 to about 1000 mg/day, and more typically from about 50to about 200 mg/day. Such dosages will be administered to a subject inneed of treatment from once to about three times each day, or more oftenas needed to effectively treat the symptoms.

It is usually preferred to administer a compound of formula I in theform of an acid addition salt, as is customary in the administration ofpharmaceuticals bearing a basic group, such as the piperidino ring. Itis also advantageous to administer such a compound by the oral route toan aging human (e.g. a post-menopausal female). For such purposes thefollowing oral dosage forms are available.

Formulations

In the formulations which follow, “Active ingredient” means a compoundof formula I.

Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared usingthe following: Ingredient Quantity (mg/capsule) Active ingredient0.1-1000  Starch, NF 0-650 Starch flowable powder 0-650 Silicone fluid350 centistokes 0- 15 

The ingredients are blended, passed through a No. 45 mesh U.S. sieve,and filled into hard gelatin capsules.

Examples of specific capsule formulations of the raloxifene that havebeen made include those shown below:

Formulation 2: Raloxifene capsule Ingredient Quantity (mg/capsule)Raloxifene 1 Starch, NF 112 Starch flowable powder 225.3 Silicone fluid350 centistokes 1.7

Formulation 3: Raloxifene capsule Ingredient Quantity (mg/capsule)Raloxifene 5 Starch, NF 108 Starch flowable powder 225.3 Silicone fluid350 centistokes 1.7

Formulation 4: Raloxifene capsule Ingredient Quantity (mg/capsule)Raloxifene 10 Starch, NF 103 Starch flowable powder 225.3 Silicone fluid350 centistokes 1.7

Formulation 5: Raloxifene capsule Ingredient Quantity (mg/capsule)Raloxifene 50 Starch, NF 150 Starch flowable powder 397 Silicone fluid350 centistokes 3.0

The specific formulations above may be changed in compliance with thereasonable variations provided.

A tablet formulation is prepared using the ingredients below:

Formulation 6: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.1-1000  Cellulose, microcrystalline 0-650 Silicon dioxide, fumed 0-650Stearate acid 0-15 

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.1-1000 mg of active ingredientare made up as follows:

Formulation 7: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.1-1000  Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5Magnesium stearate 0.5 Talc 1

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 mL dose aremade as follows:

Formulation 8: Suspensions Ingredient Quantity (mg/5 ml) Activeingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified waterto 5 mL

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

Test Procedure

Five to fifty women are selected for the clinical study. The women arepost-menopausal, i.e., have ceased menstruating for between 6 and 12months prior to the study's initiation, are in good general health, andsuffer from one or more of the above-mentioned CNS disorders. Because ofthe idiosyncratic and subjective nature of these disorders, the studyhas a placebo control group, i.e., the women are divided into twogroups, one of which receive the active agent of this invention and theother receive a placebo. Women in the test group receive between 50-200mg of the drug per day by the oral route. They continue this therapy for3-12 months. Accurate records are kept as to the number and severity ofthe above mentioned disorders in both groups and at the end of the studythese results are compared. The results are compared both betweenmembers of each group and also the results for each patient are comparedto the disorders reported by each patient before the study began.

Utility of the compounds of the invention is illustrated by the positiveimpact they have on one or more of the CNS symptoms/disorders when usedin a study as above.

We claim:
 1. A method of inhibiting one or more CNS disorders in apost-menopausal female comprising administering to a female human inneed of treatment an effective amount of a compound having the formula

wherein R¹ and R³ are independently hydrogen,

wherein Ar is optionally substituted phenyl; R² is selected from thegroup consisting of pyrrolidine, hexamthylenemino, and piperidino; or apharmaceutically acceptable salt of solvate thereof.
 2. The method ofclaim 1 wherein said compound is the hydrochloride salt thereof.
 3. Themethod of claim 1 wherein said compound is

or its hydrochloride salt.